PMID- 14741192
OWN - NLM
STAT- MEDLINE
DCOM- 20040924
LR  - 20191108
IS  - 1096-7192 (Print)
IS  - 1096-7192 (Linking)
VI  - 81
IP  - 2
DP  - 2004 Feb
TI  - Comparative genomic analysis of the HNF-4alpha transcription factor gene.
PG  - 112-21
AB  - Hepatocyte nuclear factor-4alpha (HNF-4alpha), the gene for the maturity-onset 
      diabetes of the young type 1 (MODY1) form of type 2 diabetes mellitus (T2DM), is 
      within the T2DM-linked region on chromosome 20q12-q13.1 and consequently, is a 
      positional candidate gene for T2DM. Mutations in the coding region of HNF-4alpha 
      are rare in diabetes affected subjects. Altered regulation of HNF-4alpha gene 
      expression, controlled by distant enhancer sequences, may contribute to the 
      development of type 2 diabetes. Comparative sequence analysis was performed 
      between 13 kb of genomic DNA 5' to the P1 promoter sequences of the human, mouse, 
      and rat HNF-4alpha coding sequences. Three regions, located at -10.5 kb (295 bp 
      in length), -6.25 kb (421 bp in length), and -5.36 kb (263 bp in length), have 
      significant sequence identity between the species. These three regions were 
      functionally characterized using the chloramphenicol acetyltransferase (CAT) 
      reporter assay, in which the conserved 5' regions of mouse HNF-4alpha were cloned 
      in front of the herpes simplex virus thymidine kinase promoter driving 
      transcription of the CAT gene. A fragment containing the 421 bp conserved region 
      significantly increased CAT activity in differentiated rat hepatoma cells 
      (13.7-+/-1.9-fold control), while only a modest increase in CAT activity was 
      observed in pancreatic cells (2.5-+/-0.9-fold control; 1.6-+/-0.1-fold control) 
      and dedifferentiated hepatoma cells (1.7-+/-0.4-fold control). The remaining two 
      conserved regions increased CAT activity minimally in pancreatic (1.1-+/-0.1-fold 
      control to 1.9-+/-0.1-fold control) and hepatic (1.6-+/-0.5-fold control to 
      2.3-+/-0.4-fold control) cell lines. Denaturing high-performance liquid 
      chromatography (DHPLC) was used to search for sequence variants in DNA from 259 
      T2DM individuals. Two single nucleotide polymorphisms (SNPs) were identified, 
      both of which increased CAT activity in the insulinoma cell lines in the CAT 
      reporter assay (1.4-fold increase over wild-type; 1.7-fold increase over 
      wild-type). These results suggest that comparative sequence analysis can 
      efficiently identify regulatory elements and that sequence variants in regulatory 
      elements of HNF-4alpha can contribute to altered HNF-4alpha gene expression.
FAU - Bagwell, Allison M
AU  - Bagwell AM
AD  - Department of Biochemistry, Wake Forest University, School of Medicine, 
      Winston-Salem, NC 27157, USA.
FAU - Bailly, Alain
AU  - Bailly A
FAU - Mychaleckyj, Josyf C
AU  - Mychaleckyj JC
FAU - Freedman, Barry I
AU  - Freedman BI
FAU - Bowden, Donald W
AU  - Bowden DW
LA  - eng
GR  - DK56289/DK/NIDDK NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Genet Metab
JT  - Molecular genetics and metabolism
JID - 9805456
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HNF4A protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Phosphoproteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.3.1.28 (Chloramphenicol O-Acetyltransferase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Line, Tumor
MH  - Chloramphenicol O-Acetyltransferase/genetics
MH  - Conserved Sequence
MH  - DNA-Binding Proteins/*genetics
MH  - Evolution, Molecular
MH  - Hepatocyte Nuclear Factor 4
MH  - Humans
MH  - Mice
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Phosphoproteins/*genetics
MH  - Polymorphism, Single Nucleotide
MH  - Promoter Regions, Genetic
MH  - Rats
MH  - Sequence Analysis, DNA
MH  - Transcription Factors/*genetics
EDAT- 2004/01/27 05:00
MHDA- 2004/09/25 05:00
CRDT- 2004/01/27 05:00
PHST- 2004/01/27 05:00 [pubmed]
PHST- 2004/09/25 05:00 [medline]
PHST- 2004/01/27 05:00 [entrez]
AID - S1096719203002440 [pii]
AID - 10.1016/j.ymgme.2003.10.011 [doi]
PST - ppublish
SO  - Mol Genet Metab. 2004 Feb;81(2):112-21. doi: 10.1016/j.ymgme.2003.10.011.